title: Pea3 transcription factor family members Etv4 and Etv5 mediate retrograde signaling and axonal growth of DRG sensory neurons in response to NGF.
abstract: Nerve growth factor (NGF) is a target-derived neurotrophic growth factor that controls many aspects of sensory and sympathetic neuronal development. The identification of transcription factors and downstream target genes that mediate NGF-dependent neuronal differentiation and target field innervation is currently a major challenge. Here, we show that the Pea3 transcription factor family members Etv4 and Etv5 are expressed by developing TrkA-positive dorsal root ganglion (DRG) neurons during the period of target innervation. Real-time PCR assays indicated that Etv4 and Etv5 mRNAs are significantly induced by NGF in different neuronal cells, suggesting that they could be involved in the biological responses induced by this neurotrophin. Interestingly, distal axon application of NGF in compartmentalized cultures of rat DRG sensory neurons was sufficient to induce a significant increase in Etv4 and Etv5 mRNA expression. Pharmacological assays also revealed that activation of MEK/ERK (MAPK) pathway is required for Etv4 and Etv5 gene induction in response to NGF. Downregulation of Etv4 and Etv5 using small interference RNA knockdown experiments inhibited NGF-induced neurite outgrowth of rat sensory neurons, while overexpression of full-length Etv4 or Etv5 potentiated neuronal differentiation in response to this neurotrophin. Together, these data establish Etv4 and Etv5 as essential molecules of the transcriptional program linking neurotrophin signaling to sensory neuronal differentiation, and suggest that they can be involved in NGF-mediated target innervation.
authors.affiliation: Division of Molecular and Cellular Neuroscience, Institute of Cellular Biology and Neuroscience (IBCN), CONICET-UBA, School of Medicine, Buenos Aires 1428, Argentina, and Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Paula
authors.initials: P
authors.lastname: Fontanet
authors.forename: Dolores
authors.initials: D
authors.lastname: Irala
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Alsina
authors.forename: Gustavo
authors.initials: G
authors.lastname: Paratcha
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ledda
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C510951:ETV4 protein, rat; C513243:Etv5 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D020932:Nerve Growth Factor